Poster Presentation 30th Lorne Cancer Conference 2018

Inhibition of HER2 positive breast cancer using antiandrogen therapies (#282)

James Williams 1 2 , Neil Portman 1 , Kee Ming Chia 1 3 , Alex Swarbrick 1 3 , Elgene Lim 1 3
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. School of Medicine, University of Notre Dame, Sydney, New South Wales, Australia
  3. St Vincent's Clinical School, Faculty of Medicine, UNSW, Sydney, New South Wales, Australia

Human Epidermal Growth Factor 2 (HER2) positive breast cancer accounts for nearly 25% of breast cancer and confers poor prognosis1. HER2-targeted therapies have revolutionised outcomes for patients with this subtype. However, 20-50% of patients do not respond or develop resistance to these treatments within one year2. There is an urgent need for novel therapeutic interventions in this setting. 

The androgen receptor (AR) is the most prevalent sex steroid hormone receptor in in situ, invasive and metastatic breast cancers, and 50% of HER2 positive breast cancers express AR3. There are no approved therapies targeting AR in breast cancer, but there is emerging preclinical data on its role in tumourigenesis. In AR+HER2+ breast cancer, AR mediates ligand-dependent activation of Wnt and HER2 and that specific targeting of AR, Wnt or HER2 signaling impairs androgen-stimulated tumour cell growth in vitro3,4. We propose that antiandrogen therapy presents a novel and effective therapeutic approach for the treatment of AR+HER2+ breast cancers.

We evaluated the effect on proliferation of new generation androgen receptor antagonists, ODM-201 and Enzalutamide, and the cognate agonist of AR, dihydrotestosterone (DHT), in ER-HER2+AR+ breast cancer. We established a baseline characterisation of three AR+HER2+ breast cancer cell lines (AU565, MDAMB453 and SKBR3) in terms of AR and HER2 expression, and DHT response. AR and HER2 were both expressed in all three cell lines and DHT had minimal impact on proliferation. Treatment with ODM-201 or Enzalutamide resulted in a dose-dependent inhibition of cell growth in all cell lines in the presence or absence of DHT. In the resistant setting, Enobosarm, a partial AR agonist, increased proliferation whereas, both ODM-201 and Enzalutamide suppressed proliferation in a lapatinib-resistant SKBR3 cell line.

We have provided preclinical evidence using multiple AR antagonists, that AR inhibition is antiproliferative against a panel of HER2+AR+ breast cancer cell lines. We conclude that antiandrogen therapies could be considered as an adjunct to HER2-targeted therapy in HER2-therapy naïve and resistant HER2+AR+ breast cancer.

  1. 1) Carey LA, Perou CM, Livasy CA, et.al. Race, Breast Cancer Subtypes, and Survival in the Carolina Breast Cancer Study. JAMA 2006;295(21):2492–2502.
  2. 2) Rexer BN, Arteaga L. Intrinsic and Acquired Resistance to HER2-Targeted Therapies in HER2 Gene-Amplified Breast Cancer: Mechanisms and Clinical Implications. Critical Reviews in Oncogenesis 2012:17(1);1-16.
  3. 3) Ni M, Chen YW, Lim E, Bailey ST, Imai Y, Liu XS, Brown M. Targeting Androgen Receptor in Estrogen Receptor-Negative Breast Cancer. Cancer Cell 2011;20(1):119-31.
  4. 4) Lim E, Ni Min, Hazra A, Tamini R, Brown M. Elucidating the role of Androgen receptors and breast cancer. Clinical Investigation 2012:2(10);1003-11.